JP7465861B2 - 集団におけるジアミノフェノチアジンの最適化投与 - Google Patents
集団におけるジアミノフェノチアジンの最適化投与 Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Telch, Michael J., et al. "Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia." American Journal of Psychiatry 171.10 (2014): 1091-1098:この刊行物は、恐怖消去訓練後の恐怖消去の維持及び状況記憶に対する「低用量メチレンブルー」の使用について言及している。この論文は、メチレンブルーが、低用量(0.5~4mg/kg)において神経代謝促進特性を有するジアミノフェノチアジン薬物であることを報告している。この刊行物において使用された投与量は、成人参加者に対して、4mg/kgという用量に対応する260mg/日であった。
発明者らは、患者集団においてMT化合物を投薬するための新規の薬物動態(PK)モデルを考案した。この多用途のモデルは、高齢のボランティアにおける第1相試験から誘導され、以下の実施例で説明される。
前記投与が、1日あたり、任意選択で2以上の用量に分割された、20.5~40、20.5~50、20.5~60、20.5~70、20.5~80、若しくは20.5~99、又は100mgの総1日量のMTを対象に提供し、
MT含有化合物が
の塩又はその水和物若しくは溶媒和物である方法が開示される。
(i)前記対象に、MT含有化合物を第1の期間経口投与することであって、前記投与が、任意選択で2以上の用量に分割された、1日あたり1~10mg、任意選択で1日あたり8mgの総1日量のMTを対象に与える、経口投与すること;
(ii)前記対象に、MT含有化合物をその直後の期間経口投与することであって、前記投与が、任意選択で2以上の用量に分割された、1日あたり20.5~40mg、20.5~60、20.5~80、又は20.5~100mg、任意選択で1日あたり約21~40、50、又は60mgの総1日量のMTを対象に与える、経口投与すること;
(iii)任意選択で、(ii)の処置を、AChEI及び/又はメマンチンなど、アセチルコリン又はグルタミン酸神経伝達物質の活性の調節物質である神経伝達調節化合物の投与と併用すること。
好ましくは、LMT化合物は国際公開第2007/110627号又は国際公開第2012/107706号に記載されているタイプの「LMTX」化合物である。
無機酸:ヒドロハライド酸(例えば、HCl、HBr)、硝酸(HNO3)、硫酸(H2SO4)
有機酸:炭酸(H2CO3)、酢酸(CH3COOH)、メタンスルホン酸、1,2-エタンジスルホン酸、エタンスルホン酸、ナフタレンジスルホン酸、p-トルエンスルホン酸
が挙げられる。
無水塩は、およそ477.6という分子量を有する。LMTコアに対する285.1という分子量に基づくと、本発明においてこのMT化合物を使用する場合の重量因子(weight factor)は、1.67である。「重量因子」とは、MT含有化合物が含んでいるMTの重量に対する純粋なMT含有化合物の相対的な重量を意味する。
当業者が認識するように、所与の1日投与量に対して、より頻繁な投薬は、より大きな薬物蓄積をもたらし得る。
用語「処置」は、ある状態を処置する文脈において本明細書中で使用されるとき、ヒト又は動物(例えば、獣医学的適用)にかかわらず、ある所望の治療効果、例えば、その状態の進行の阻害が達成される処置及び治療に広く関し、進行速度の低下、進行速度の停止、状態の後退、状態の回復及び状態の治癒を含む。
用語「処置」は、同じ神経変性障害に対して2つ以上の処置又は治療が、例えば、連続的又は同時に組み合わされる、「併用」処置及び「併用」療法を含む。これらは、対症療法であり得るか、又は疾患調節性療法であり得る。
本明細書中に記載される神経変性障害の処置の場合、低用量のMT化合物に基づく処置レジメンは、好ましくは長期にわたり得る。特定の持続時間は、医師の判断により決定され得る。
少なくとも1、2、3、4、5、6、7、8、9、10、11、12ヶ月又はそれ以上。
少なくとも2、3、4、5年又はそれ以上。
6~12ヶ月。
1~5年。
であり得る。
本明細書に記載の方法(投与レジメン)を利用して、具体的な特定の処置的又は予防的なアウトカムを達成することができる。その具体的なアウトカムは、神経変性障害に関連する尺度に従って定量化することができる。そのような尺度は、例えば、障害に関連する認知上の、機能的な、又は身体的基準の変化を測定し得る。本明細書の実施例は、プラセボ又は他の基準点(例えば、異なる投与レジメン)と比べて投与レジメンの効果が確認され得る適切な尺度を説明する。これらには、ADに関連して使用されるアルツハイマー病評価尺度-認知機能下位尺度(ADAS-cog)及びbvFTDに関連して使用されるアデンブルック認知機能検査-改訂版(ACE-R)がある。
各場合に本発明に従って処置されていない対応する対照又は対照集団と比べて、
(i)任意選択で、52週間にわたるアデンブルック認知機能検査-改訂版(ACE-R)尺度での低下における少なくとも1、2、3、4、5、6、7、若しくは8点の減少である、対象の認知機能低下の減少;又は(ii)任意選択で、52週間にわたる機能的活動質問票(FAQ)での低下における少なくとも1、2、3、4、5、若しくは6点の減少である、対象の機能的低下の減少。
本発明のMT化合物又はそれを含む薬学的組成物は、対象/患者に経口投与される。
いくつかの実施形態において、投与単位は、カプセルである。
本発明のMT含有組成物は、適切な用量の本明細書に記載のMT化合物を含む「栄養補助組成物」中に、1つ以上の栄養素と組み合わせて可食の形態(例えば、経口剤形)で存在することができる。
B-ビタミン補給(葉酸[葉酸塩、ビタミンB9]、ビタミンB12、ビタミンB6)は、ADプロセスの重要な構成要素であり認知機能低下に関連する特定の脳領域の萎縮を遅くできることが報告されている。これは、特に、ホモシステインレベルが高い高齢の対象の場合である(Douaud, Gwenaelle, et al. "Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment." Proceedings of the National Academy of Sciences 110.23 (2013): 9523-9528; Quadri, Pierluigi, et al. "Homocysteine, folate, and vitamin B12in mild cognitive impairment, Alzheimer disease, and vascular dementia." The American journal of clinical nutrition 80.1 (2004): 114-122; Rosenberg IH, Miller JW. Nutritional factors in physical and cognitive functions of elderly people. The American journal of clinical nutrition. 1992 Jun 1;55(6):1237S-1243S.も参照のこと)。
微量栄養素又は抗酸化物質、例えば、ポリフェノールが、神経変性疾患、特に、認知障害及びADを含む加齢性疾患の保護又は処置に関して利点を有すると報告されている。
・非フラボノイドポリフェノール、つまり、リスベラトロール及びクルクミン、
・カロテノイド、つまり、リコピン、ルテイン、ゼアキサンチン、β-クリプトキサンチン、α-カロテン、及び最も著名なカロテノイドであるβ-カロテン、
・クロシン(サフランにおいて同定された主要な化学的化合物)、
・ジテルペン(例えば、カルノシン酸及びロスマリン酸は、ローズマリーにおける最も重要な抗酸化化合物のうちの2つである)
が挙げられる。
微量栄養素及び抗酸化物質に関して上記に記載された又は相互参照される植物に加えて、他の植物抽出物及びハーブも、CNS障害において利点を有すると報告されている。Kumar, Vikas. "Potential medicinal plants for CNS disorders: an overview." Phytotherapy Research 20.12 (2006): 1023-1035を参照のこと。これらには、Ginkgo biloba、Hypericum perforatum(セイヨウオトギリソウ)、カバカバとも呼ばれるPiper methysticum Forst.(コショウ科)、Valeriana officinalis L.(セイヨウカノコソウ)、Bacopa monniera(インドの現地ではBrahmi又はJalanimbaとして知られている)、Convolvulus pluricaulis(Shankhpushpi又はshankapushpiとしても知られる)が含まれる。
例えば、ω-3ポリ不飽和脂肪酸(PUFA)が、加齢性の脳変性を予防するための有望なツールであり得ることが報告されている。PUFA、例えば(ドコサヘキサエン酸(DHA、22:6)及びエイコサペンタエン酸(EPA、20:5)の起源としては、魚油が挙げられる(Denis, I., et al. "Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms." Ageing research reviews 12.2 (2013): 579-594)。
本発明の教示は、例えば、動物、哺乳動物、有胎盤類、げっ歯類(例えば、モルモット、ハムスター、ラット、マウス)、ネズミ科の動物(例えば、マウス)、ウサギ目の動物(例えば、ウサギ)、鳥類(例えば、鳥)、イヌ科の動物(例えば、イヌ)、ネコ科の動物(例えば、ネコ)、ウマ科の動物(例えば、ウマ)、豚のような動物(例えば、ブタ)、羊のような動物(例えば、ヒツジ)、ウシ亜科の動物(例えば、ウシ)、霊長類、猿のような動物(例えば、サル又は類人猿)、サル(例えば、マーモセット、ヒヒ)、単孔類(例えば、カモノハシ)、類人猿(例えば、ゴリラ、チンパンジー、オランウータン、テナガザル)又はヒトでである対象/患者に適用することができる。
その方法は、対象に本明細書に記載の用量でメチルチオニニウム(MT)含有化合物を経口投与する工程を含み、
前記処置は、アセチルコリンエステラーゼ阻害剤又はN-メチル-D-アスパラギン酸レセプターアンタゴニストのどちらか又はその両方の投与を更に含む。
本明細書中に記載される単位投与量組成物(例えば、低用量MT含有化合物及び任意に他の成分又はADの処置のためのより一般的なMT組成物)は、ラベルされた包装容器の中にその使用についての指示書とともに提供され得る。
本発明の1つの態様は、タンパク質の凝集、例えば、神経変性疾患及び/又は臨床認知症に関連するタンパク質の凝集を制御する(例えば、後退させる及び/又は阻害する)ための、本明細書中に記載されるようなMT化合物又は組成物の使用である。その凝集は、下記で論じられるような疾患状態に関連し得る。
本発明の別の態様は、上記で説明したように、処置方法に関し、その方法は、予防有効量又は治療有効量の本明細書中に記載されるような化合物を好ましくは薬学的組成物の形態で、処置を必要とする患者に投与する工程を含む。
本発明の別の態様は、治療によってヒト又は動物の身体を処置する方法(例えば、疾患の状態を処置する方法)において使用するための本明細書中に記載されるような化合物又は組成物に関する。
本発明の別の態様は、処置(例えば、疾患の状態の処置)において使用するための医薬品の製造における、本明細書中に記載されるようなMT化合物又は組成物の使用に関する。
本明細書に記載の発見は、異なる疾患におけるMT化合物の投与について密接な関係を有する。特に、MT濃度がCmax閾値を超える対象の割合を最大化しつつ、望ましい臨床プロファイルを維持するための比較的低用量を維持する投与レジメンの採用を、MTが有効であるとされているタンパク質凝集の様々な疾患の予防の治療に適用することができる。
本発明の好ましい実施形態は、タウタンパク質に基づく。用語「タウタンパク質」は、本明細書中で使用されるとき、タウタンパク質ファミリーの任意のタンパク質のことを広く指す。タウタンパク質は、集合と脱集合のサイクルの反復中に微小管とともに同時精製するたくさんのタンパク質ファミリーの中の1つとして特徴づけられ(例えば、Shelanski et al., 1973, Proc. Natl. Acad. Sci. USA, Vol. 70, pp. 765-768を参照のこと)、微小管結合タンパク質(MAP)として知られている。タウファミリーのメンバーは、特徴的なN末端セグメント、そのN末端セグメントに挿入された脳において発生的に制御されるおよそ50アミノ酸の配列、31~32アミノ酸の3又は4つのタンデム反復からなる特徴的なタンデム反復領域、及びC末端テイルを有するという共通の特徴を共有する。
1つの実施形態において、本発明は、アルツハイマー病(AD)、例えば、軽度、中等度又は重度のADの処置のために使用される。
MTは、家族性ALSと孤発性ALSの両方の大部分の病理学的特徴でありFTLD-Pの特徴でもある細胞内のTDP-43タンパク質凝集を標的化し、それを減少させ得る作用様式を有する。
MTは、ハンチントン病の病理学的特徴である細胞内のポリグルタミンタンパク質凝集を減少させ得る。ハンチントン病は、ハンチンチンのN末端に位置する翻訳されるCAGリピートの拡大が原因である。野生型染色体は、6~34個のリピートを含むのに対して、ハンチントン病では、染色体は36~121個のリピートを含む。発症年齢は、タンパク質内のポリグルタミンリピートをコードするCAGトラクトの長さと逆相関する。
ミトコンドリア障害、特に呼吸鎖疾患(RCD)において最も高頻度で影響される器官は、骨格筋に加えて、中枢神経系(CNS)である。RCDのCNS所見は、脳卒中様エピソード、癲癇、片頭痛、運動失調、痙縮、運動障害、精神障害、認知機能低下又はさらには認知症(ミトコンドリア認知症)を含む。これまで、ミトコンドリア認知症は、MELAS、MERRF、LHON、CPEO、KSS、MNGIE、NARP、リー症候群及びAlpers-Huttenlocher病において報告されてきた(Finsterer, 2009)。ミトコンドリアの呼吸鎖には、一連の電子伝達に関わる複合体が4つある。これらの複合体のいずれかの異常な機能によって、異常な電子伝達鎖及びその後の異常なミトコンドリア呼吸に続発するミトコンドリア病がもたらされ得る。ミトコンドリア呼吸鎖の複合体IIIは、シトクロムcに電子を伝達するように作用する。
本発明において使用されるLMT含有化合物は、合成中の「不純物」として酸化型(MT+)化合物を含むことがあり、また、合成後に酸化(例えば、自動酸化)して、対応する酸化型を生じ得る。したがって、本発明の化合物を含む組成物が少なくともいくらかの対応する酸化型化合物を不純物として含むことは不可避ではないにしてもあり得ることである。例えば、「LMT」塩は、15%までの、例えば10~15%の、MT+塩を含み得る。
本明細書中に記載されるMT含有化合物は、それ自体が塩であるが、混合塩の形態でも(すなわち、本発明の化合物を別の塩とともに)提供され得る。そのような混合塩は、用語「及びその薬学的に許容される塩」によって包含されると意図される。別段特定されない限り、特定の化合物に対する言及は、その塩も包含する。
実施例1-MT含有化合物の提供
本明細書に記載のMT含有化合物の化学合成の方法は当技術分野に公知である。例えば:
化合物1~7の合成は、国際公開第2012/107706号に記載の方法又はそれらに類似の方法に従って実施できる。
AD対症療法としては、脳内のシナプス神経伝達を直接調節するものがあり、アセチルコリンエステラーゼ阻害剤(AChEI)又はNMDA受容体アンタゴニストとして市販されている。
初期モデルにおいて(示さず)、全MT部分(親MT、デスメチルMT、及びLMT-コンジュゲート)の動態を、マルチコンパートメントモデルにより同時に特性化した。経口投与後の親MTの動態を、結合が血漿及び組織コンパートメント中で起こり、遅延した吸収が2つのトランジットコンパートメントにより起こる2-コンパートメントモデルにより適切に記述した。このモデルは固定されたVcを有する。用量の増加と共に、吸収速度がより緩徐になる傾向があったが、それは、用量依存性吸収速度定数(Ka)を使用してモデルに組み込まれる。親MTの見かけの経口クリアランス(CL/F)は、親CLにおける変動性のごく一部が正規化されたクレアチニンクリアランス(CLCRN)により記述されるように、腎機能に関連していた。親MTのより少ない一部分はデスメチルMTに代謝され、デスメチルMTの動態は、線形消失を伴う2-コンパートメントモデルにより記述された。親MTはLMT-グルクロニドにも転化され、その動態は、線形消失を伴う1-コンパートメントモデルにより記述された。重要なことには、LMT-コンジュゲートの一部は腸肝再循環(EHR)を受け、それは、脈動パターンの胆汁分泌を伴う潜在性胆嚢コンパートメント(latent gallbladder compartment)により生理学的に模倣された。
第3相AD試験「005」及び「015」の試験設計は、国際公開第2018/019823号の実施例4及び3にそれぞれ記載されており、実施例はその結果についても議論している。それらの実施例の開示は、参照により本明細書に具体的に組み込まれている。簡潔に言うと、それらの第3相試験は、高用量のLMTM(150~250mg/日)を、起こり得る尿変色のマスクとして意図された低用量(8mg/日)と比較したものであった(Gauthier 2016; Wilcock 2018)。これらは、臨床及び脳画像化評価項目での疾患進行を遅延させることにおける、特に単独療法としてのLMTMの潜在的な有用性及び高用量が8mg/日用量を超える潜在的な利益を与えなかったことを示した。
混合効果・反復測定モデル(Mixed effect Model Repeat Measurement)(MMRM)手法を利用し、次いで、試験005及び015の単独療法又はアドオン療法としてのプールされた8mg/日用量の65週間にわたるADAS-cog変化を、「高Cmax」群及び「低Cmax」群に関して、各場合に、LMTMを単独療法として投与されたものと対症療法(AChEI及び/又はメマンチン)と併用して(「アドオン」)投与されたものに分けて計算した。結果を、同じデータを示す図3a及び3bに示す。対症療法を使用した患者を、「Achmem」と示す。
LMTMの3つの第3相二重盲検比較試験が完了した(それぞれ軽度及び軽度から中等度のADを有する対象のものが1つずつ並びにbvFTDを有する対象のものが1つ)。AD試験の結果は公表されている(Gauthier et al., 2016; Wilcock et al., 2018)。
利用可能なデータから、Cmax効果は、側頭葉FDG-PET低下を評価する際には見られなかった。この尺度に関して、いくつかの単独療法の利益がそのままであったものの、高用量LMTM(プールされた200mg/日)が、実際には、そうでなければLMTM単独療法で見られた利益を弱めたようであった(データ示さず)。
要約すると、PKモデルが、注意深くサンプリングされた第1相試験から得られたデータに基づいて開発された。この対象ごとの(per-subject)定常状態から、Cmaxを推定し、それを使用して、8mg/日用量を服用した患者を高(中央値より上)Cmax群及び低(中央値より下)Cmax群に分けた。予想外にも、高Cmax群と低Cmax群は、認知機能低下が(ADAS-cogを使用して評価して)およそ2.5単位異なり、効果は単独療法群とアドオン処置群の両方に観察された。興味深いことに、高用量でFDG-PETに関して逆の用量-反応関係の証拠があった。
1 単独療法に対してアドオン処置状態
2 所与の用量に対してすら対象集団内で様々である血漿濃度。
4mg1日2回では、50%の対象がCmax閾値より上にあり、プラセボに対する予測される処置効果は65週間にわたるおよそ5ADAS-cog単位である。
行動障害型前頭側頭型認知症(bvFTD)におけるLMTMの第3相試験の試験設計は、国際公開第2018/041739号の実施例3~10に記載されており、その実施例はそれらの結果も議論している。それらの実施例の開示は、参照により具体的に本明細書に組み込まれている。
統計分析の実施を可能とする、より情報を与える手法は、8mg/日の用量でLMTMを投与された患者を、第1日の第1の投与の後に検証済みの定量限界より低い血漿レベルを有する35%の患者に相当する(0.2~10ng/ml;N=208)最低35%の患者の上限を画定する閾値を使用してCmax,ssに基づいて分類することである。その閾値は0.373ng/mL未満である。
0.373ng/mlの閾値による患者の分割に基づくと、8mg/日用量を投与された患者の処置の差は-3.4ADAS-cog単位である(以下の表EX4参照;およそ2~3ADAS-cog単位を示す中央値折半に関する実施例8参照):
さらなる検討事項は、患者が、LMTMを単独で投与されるか、認可されたADの処置(AChEI及び/又はメマンチン)と併用して投与されるかである。8mg/日用量を投与された患者を、これらの薬物との同時投薬状態によりさらに調査した。以下の表EX5に見られる通り、0.373ng/mlの閾値より下の定常状態血漿レベルを有する患者と、それより上の定常状態血漿レベルを有する患者との差は、LMTMが単独療法として服用されるかアドオン療法として服用されるかにかかわらず、認知(ADAS-cog)及び脳萎縮(LVV及びWBV)評価項目で統計的有意性に達する。
65週間にわたるADAS-cog低下のさらなる分析を、65週間にわたる予想される処置反応のための最小及び最大の血漿濃度を推定するために、改変された形態のヒルの式(Wagner, 1968)を使用して実施した。ヒルの式を、非協同性の仮定の下に適用し、データの目視検査に基づき0.29ng/mlのCmax,ss濃度で無効化レベルを11単位とする強制された全体的なゼロ(imposed overall zero)値を使用した。異なる限界値の使用は、意味があるように結果を変化させなかった。さらに、線形項を加えて、150~250mg/日の範囲の用量のデータを使用して、高濃度で起こっている傾向がモデルに含まれるようにした。拡張されたヒルの式を、以下の形でデータに適用した:
パラメーターの変化=Emin-(Emax *([C]-0.29))/(EC50+([C]-0.29))+(A*([C]-0.29))
式中、Eminは強制されたゼロ値であり、Emaxは、標準的なヒルの式中で仮定される最大の処置効果であり、EC50は処置効果が標準的なヒルの式において仮定される最大の50%であるCmax,ssであり、Aは、潜在的な二相性の反応を考慮するために、モデルにより推定されるさらなる線形項である。Cmax,ssを、線形モデルを8、150、200、及び250mg/日用量での平均血漿濃度にフィットさせることにより得られた関係を使用して、等価な平均用量推定値としても表した:
用量推定値(mg/日)=0.045*Cmax,ss+0.016。
前記から明らかである通り、LMTMが対症療法と併用される場合LMTMの最大効果の減少がある。しかし、これが、対症療法薬による慢性の事前処置を背景として患者にLMTMが投与された状況に関連していることに留意すべきである。この機序は、充分に特性化されているタウ遺伝子導入マウスモデルでの一連の実験において解明された。これらの動物がコリンエステラーゼ阻害剤(リバスチグミン)により慢性的に治療されている場合、LMTMが単独で投与される場合に見られるほとんど全ての神経生物学的効果は減少するか又は完全になくなり、空間学習記憶に対するLMTMの有益な効果がなくなる。同様にメマンチンによる事前処置は、空間学習記憶に対する効果をなくした(結果示さず)。
最低の35%群(第1日の検証済み定量限界より下の血漿レベルを有する患者のパーセンテージに相当する)の上限を画定するカットオフは、bvFTD集団では0.346ng/mlであった。
上記図18からわかる通り、全アウトカムで、処置効果は200mg/日の高用量で悪く、bvFTDにおける二相性の濃度-反応関係を意味する。
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Claims (21)
- ヒト対象の神経変性障害の治療的処置の方法のための、メチルチオニニウム(MT)含有化合物を含む治療組成物であって、
前記治療組成物が、前記対象に、前記治療組成物であるMT含有化合物を経口投与することを含み、
前記投与が、1日あたり、任意選択で2以上の用量に分割された、20.5~60mgの総1日量のMTを前記対象に与え、
前記MT含有化合物が
以下の式:
前記障害が、アルツハイマー病;ピック病、進行性核上性麻痺、脱抑制-認知症-パーキンソニズム-筋萎縮複合、淡蒼球橋黒質変性症、Guam-ALS症候群、淡蒼球黒質ルイ体変性症、大脳皮質基底核変性症、好銀性顆粒認知症、拳闘家認知症又は慢性外傷性脳障害、ダウン症候群、亜急性硬化性全脳炎、ニーマン・ピック病C型、サンフィリポ症候群B型又は筋緊張性ジストロフィDM1若しくはDM2からなるリストから選択される、治療組成物。 - 前記総1日投与量が、21~40mg;21~32mg;又は24~32mgである、請求項1に記載の治療組成物。
- 前記総1日量が、20.5、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40mgである、請求項1に記載の治療組成物。
- 前記総1日量の前記MT含有化合物が、1日1回投与されるか、分割用量として、1日2回又は1日3回投与される、請求項1~3のいずれか一項に記載の治療組成物。
- 前記対象が、
(a)アセチルコリンエステラーゼ阻害剤若しくはN-メチル-D-アスパラギン酸受容体アンタゴニストによる処置を受けた履歴がないか、
(b)アセチルコリンエステラーゼ阻害剤若しくはN-メチル-D-アスパラギン酸受容体アンタゴニストによる処置を受けた履歴があるが、その処置を、前記MT含有化合物による処置の少なくとも1、2、3、4、5、6、7日前、若しくは2、3、4、5、6、7、8週間前に停止したか、又は、
(c)アセチルコリンエステラーゼ阻害剤若しくはN-メチル-D-アスパラギン酸受容体アンタゴニストによる処置を受けている対象として選択され、前記処置が前記MT含有化合物による処置の前に中止される、
請求項1~4のいずれか一項に記載の治療組成物。 - 前記治療的処置が、アセチルコリンエステラーゼ阻害剤又はN-メチル-D-アスパラギン酸受容体アンタゴニストと併用されない、請求項1~5のいずれか一項に記載の治療組成物。
- 前記治療的処置が、アセチルコリンエステラーゼ阻害剤又はN-メチル-D-アスパラギン酸受容体アンタゴニストと併用される、請求項1~5のいずれか一項に記載の治療組成物。
- アセチルコリンエステラーゼ阻害剤が、ドネペジル;リバスチグミン;及びガランタミンからなるリストから選択され、及び/又は、前記N-メチル-D-アスパラギン酸受容体アンタゴニストがメマンチンである、請求項5~7のいずれか一項に記載の治療組成物。
- 前記障害がアルツハイマー病である、請求項1~8のいずれか一項に記載の治療組成物。
- 前記処置が、明記された投与量の前記MT含有化合物である第1の薬剤を、
アミロイド前駆体タンパク質からβ-アミロイドへのプロセシングの阻害剤である第2の薬剤と組み合わせる併用療法である、請求項9に記載の治療組成物。 - 前記処置が、下記:
(i)前記対象に、前記MT含有化合物を第1の期間経口投与することであって、前記投与が、1日あたり1~10mgの総1日量のMTを前記対象に与える、経口投与であること;
(ii)前記対象に、前記MT含有化合物をさらなる期間経口投与することであって、前記投与が、1日あたり20.5~60mgの総1日量のMTを前記対象に与える、経口投与であること
を含む処置レジメンの一部である、請求項9又は10に記載の治療組成物。 - 前記MT含有化合物が以下の式:
- 前記MT含有化合物が以下の式:
を有する、請求項1~11のいずれか1項に記載の治療組成物。 - 前記MT含有化合物が以下の式:
- 前記MT含有化合物が以下の式:
- 前記又は各プロトン酸が無機酸である、請求項1~15のいずれか一項に記載の治療組成物。
- 各プロトン酸がヒドロハライド酸である、請求項16に記載の治療組成物。
- 前記又は各プロトン酸が有機酸である、請求項1~15のいずれか一項に記載の治療組成物。
- 前記又は各プロトン酸が、H2CO3;CH3COOH;メタンスルホン酸、1,2-エタンジスルホン酸、エタンスルホン酸、ナフタレンジスルホン酸、p-トルエンスルホン酸から選択される、請求項16又は18に記載の治療組成物。
- 前記MT含有化合物が
- 前記MT含有化合物が、下記:
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